FERROUS ION STRONGLY PROMOTES THE RING-OPENING OF THE HYDROLYSIS INTERMEDIATES OF THE ANTIOXIDANT CARDIOPROTECTIVE AGENT DEXRAZOXANE (ICRF-187)

The ferrous- and ferric-ion-promoted hydrolysis of the doxorubicin cardioprotective agent dexrazoxane (ICRF-187) has been studied spectrophotometrically and by HPLC. While dexrazoxane itself did not undergo any iron-promoted ring-opening hydrolysis, both ferrous (t(1/2) 0.4 min) and ferric (t(1/2) 170 min) ions promoted, by factors of up to 6000 and 8, respectively, the hydrolysis of the one-ring open intermediates of dexrazoxane to yield the strongly metal-ion-chelating form, The pH dependence of both the ferrous- and ferric-ion-promoted hydrolysis of one of the one-ring open intermediates was studied and was consistent with base-catalyzed hydrolysis. In each case, due to the problem of proton ambiguity in the rate law, a bimolecular reaction with external hydroxide could not be distinguished from an intramolecular reaction of hydroxide bound to iron. The mechanism of the cardioprotective effects of dexrazoxane may involve enzymatic or nonenzymatic hydrolysis to the one-ring open intermediates. Thus, these intermediates may be the active forms of the drug that may be acting by either displacing iron from the iron-doxorubicin complex or chelating loosely bound iron and then undergoing a rapid metal-ion-promoted hydrolysis to their strongly chelating forms, Thus, the ability of iron to participate in site-specific hydroxyl radical damage may be reduced. (C) 1995 Academic Press, Inc.